title: Investigation of aryl halides as ketone bioisosteres: refinement of potent and selective inhibitors of human cytochrome P450 19A1 (aromatase).
abstract: Bioisosteric replacement of cyclic ketone functionality with aryl halides was investigated on a centrally-flexible, five-component 1,2,3-triazole-containing pharmacophore, resulting in enhanced inhibition of aromatase (CYP450 19A1). Structure-activity data generated from both syn- and anti-aldol precursors provides significant insights into the requirements for enhanced potency, validating this novel ketone-to-aryl halide bioisostere hypothesis.
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ont. L8S 4M1, Canada. Electronic address: jmcnult@mcmaster.ca.
authors.forename: James
authors.initials: J
authors.lastname: McNulty
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Nielsen
authors.forename: Carla E
authors.initials: CE
authors.lastname: Brown
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: DiFrancesco
authors.forename: Nesrin
authors.initials: N
authors.lastname: Vurgun
authors.forename: Jerald J
authors.initials: JJ
authors.lastname: Nair
authors.forename: Denis J
authors.initials: DJ
authors.lastname: Crankshaw
authors.forename: Alison C
authors.initials: AC
authors.lastname: Holloway
mesh_terms: D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D001555:Benzene Derivatives / Q000737:chemistry* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology; D005260:Female; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000737:chemistry* / Q000494:pharmacology; D007536:Isomerism; D007659:Ketones / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D047072:Aromatase Inhibitors; D001555:Benzene Derivatives; D006846:Hydrocarbons, Halogenated; D007659:Ketones; D014230:Triazoles; D001141:Aromatase; C561410:CYP19A1 protein, human
keywords: Anticancer activity; Aromatase; Bioisosterism; Breast cancer